scholarly journals Adjudicating mild cognitive impairment due to Alzheimer’s disease as a novel endpoint event in the TOMMORROW prevention clinical trial

2021 ◽  
Author(s):  
Lon S Schneider ◽  
David A. Bennett ◽  
Martin R. Farlow ◽  
Elaine R. Peskind ◽  
Murray A. Raskind ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Primary Endpoint ◽  
Prevention Trial ◽  
Endpoint Event ◽  
Independent Review ◽  
Prevention Trials ◽  
Ad Prevention ◽  
Stage 1 ◽  
Adjudication Committee

Abstract Background The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer’s disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. Methods The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant’s clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI or AD proceeded through up to three review stages – independent review, collaborative review, and full committee review – requiring a unanimous decision and ratification by the chair. Results Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators’ clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80–90% for the remainder of the study. Conclusions The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure. Trial registration: NCT01931566

P1-050: ADJUDICATING MILD COGNITIVE IMPAIRMENT DUE TO ALZHEIMER'S DISEASE AS A NOVEL ENDPOINT EVENT IN THE TOMMORROW STUDY: A DELAY-OF-ONSET PHASE 3 CLINICAL TRIAL

2006 ◽  
Vol 14 (7S_Part_5) ◽  
pp. P286-P286
Author(s):  
Carl Chiang ◽  
Robert Alexander ◽  
Kathleen A. Welsh-Bohmer ◽  
Brenda L. Plassman ◽  
Heather Romero ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Phase 3 ◽  
Endpoint Event ◽  
Onset Phase

scholarly journals APOE-related risk of mild cognitive impairment and dementia for prevention trials: An analysis of four cohorts

PLoS Medicine ◽  
2017 ◽  
Vol 14 (3) ◽  
pp. e1002254 ◽  
Author(s):  
Jing Qian ◽  
Frank J. Wolters ◽  
Alexa Beiser ◽  
Mary Haan ◽  
M. Arfan Ikram ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Related Risk ◽  
Prevention Trials

scholarly journals ImproveCog, a cognitive stimulation program for people with mild cognitive impairment and dementia: First stage of development

Psicologia ◽  
2021 ◽  
Vol 35 (2) ◽  
pp. 27-44
Author(s):  
Laura Meireles ◽  
Selene G. Vicente
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Health Professionals ◽  
Research Council ◽  
Medical Research Council ◽  
Cognitive Stimulation ◽  
Individual Interviews ◽  
Clinical Phase ◽  
Stage Of Development ◽  
Stage 1

Cognitive stimulation seems to be an important tool to slow the rate of cognitive decline due to dementia. This study describes the development of a cognitive stimulation program (ImproveCog) for people with Mild Cognitive Impairment, Alzheimer’s Disease, and behavioral variant Frontotemporal Dementia, within the Medical Research Council framework. Stage 1 established the theoretical and evidence basis of the program through a review of the existing cognitive stimulation programs as well as cognitive exercises and their efficacy (Pre-Clinical Phase) and includes qualitative testing through five focus group with eighteen health professionals and twelve individual interviews with people with cognitive impairment (Phase I - Modeling). An initial version of the program, which consisted of twelve 90-min weekly sessions and included a manual with cognitive stimulation exercises to be performed at home, was ready to be implemented in a pilot study to create a final version of ImproveCog.

scholarly journals THE ROAD AHEAD TO CURE ALZHEIMER\'S DISEASE: DEVELOPMENT OF BIOLOGICAL MARKERS AND NEUROIMAGING METHODS FOR PREVENTION TRIALS ACROSS ALL STAGES AND TARGET POPULATIONS

2014 ◽  
pp. 1-22
Author(s):  
E. Cavedo ◽  
S. Lista ◽  
Z. Khachaturian ◽  
P. Aisen ◽  
P. Amouyel ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Secondary Prevention ◽  
Diagnostic Criteria ◽  
Biological Markers ◽  
Genetic Risk ◽  
Preclinical Ad ◽  
Prodromal Ad ◽  
Prevention Trials

Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1- 40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for “prodromal AD” and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.

GRK5 Deficiency Causes Mild Cognitive Impairment due to Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
William Z. Suo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Prodromal Stage ◽  
Health Crisis ◽  
Disease Modifying Therapy ◽  
Clinical Observations ◽  
Ad Prevention ◽  
G Protein Coupled

Prevention of Alzheimer’s disease (AD) is a high priority mission while searching for a disease modifying therapy for AD, a devastating major public health crisis. Clinical observations have identified a prodromal stage of AD for which the patients have mild cognitive impairment (MCI) though do not yet meet AD diagnostic criteria. As an identifiable transitional stage before the onset of AD, MCI should become the high priority target for AD prevention, assuming successful prevention of MCI and/or its conversion to AD also prevents the subsequent AD. By pulling this string, one demonstrated cause of amnestic MCI appears to be the deficiency of G protein-coupled receptor-5 (GRK5). The most compelling evidence is that GRK5 knockout (GRK5KO) mice naturally develop into aMCI during aging. Moreover, GRK5 deficiency was reported to occur during prodromal stage of AD in CRND8 transgenic mice. When a GRK5KO mouse was crossbred with Tg2576 Swedish amyloid precursor protein transgenic mouse, the resulted double transgenic GAP mice displayed exaggerated behavioral and pathological changes across the spectrum of AD pathogenesis. Therefore, the GRK5 deficiency possesses unique features and advantage to serve as a prophylactic therapeutic target for MCI due to AD.

Toward Identifying Mild Cognitive Impairment in Hispanic and African American Adults

2017 ◽  
Vol 2 (2) ◽  
pp. 110-116
Author(s):  
Valarie B. Fleming ◽  
Joyce L. Harris
Keyword(s):  
Older Adults ◽  
African American ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Healthcare Access ◽  
Communication Disorders ◽  
Healthcare Systems ◽  
Prevention Education ◽  
Education Management ◽  
African American Adults

Across the breadth of acquired neurogenic communication disorders, mild cognitive impairment (MCI) may go undetected, underreported, and untreated. In addition to stigma and distrust of healthcare systems, other barriers contribute to decreased identification, healthcare access, and service utilization for Hispanic and African American adults with MCI. Speech-language pathologists (SLPs) have significant roles in prevention, education, management, and support of older adults, the population must susceptible to MCI.

Diagnoseeröffnung und Begleitung

2015 ◽  
Vol 72 (4) ◽  
pp. 225-231
Author(s):  
Irene Bopp-Kistler
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Case Management ◽  
Sich Eine ◽  
Jüngere Patienten ◽  
Soziale Situation

Vor der Diagnoseeröffnung geht sowohl für die Demenzerkrankten, wie aber auch für ihre Angehörigen eine lange Zeit der Unsicherheit, der Verunsicherung, der Angst, der Zweifel, aber auch von Konflikten voraus. Der Beginn einer neurodegnerativen Erkrankung ist immer mit sehr vielen offenen Fragen verbunden. Wenn jüngere Patienten noch im Berufsleben stehen, löst bereits das Stadium des Mild Cognitive Impairment Fehlleistungen, Burnout, Mobbing, Depression und Krankschreibung aus. In der Partnerschaft entstehen Konflikte und Schuldzuweisungen. Es ist viel zu wenig bekannt, dass meist diese Probleme auf Beziehungsebene belastender sind als die typischen Defizite, die auf die Demenzerkrankung zurückzuführen sind. Es besteht leider immer noch die Meinung, dass sich eine Abklärung und Diagnosestellung nur bei Krankheiten lohnt, die auch behandelbar sind. Ziel jeder evidenzbasierten Medizin sollte es aber sein, den Patienten und ihren Angehörigen eine möglichst gute Lebensqualität zu geben. Und diese Forderung ist besonders bezüglich Demenzdiagnose zu stellen. Ein offenes Diagnoseeröffnungsgespräch ermöglicht es den Patienten und ihren Angehörigen, sich mit der Situation auseinander zu setzen, miteinander Lösungsstrategien zu suchen in der herausfordernden Situation einer Demenzerkrankung, die immer das ganze familiäre und soziale System betrifft. Der Patient hat das Recht auf Information über seine Diagnose, das gilt auch für die Demenzerkrankten. Das Diagnosegespräch erfordert Zeit und höchste Professionalität, das Wissen um die individuellen Defizite und Ressourcen, die soziale Situation und die Biographie und Persönlichkeit der Patienten, aber auch ihrer Angehörigen. Das Diagnosegespräch löst viele Emotionen aus, es ist wichtig auf diese einzugehen und diese auch aufzunehmen. Primär sollte mit dem Patienten gesprochen werden, aber möglichst im Beisein der Angehörigen, wichtig dabei ist die Wertschätzung des Demenzerkrankten auch bei Anosognosie. Den Angehörigen sollten nicht Ratschläge gegeben werden, sondern es sollte in einem therapeutischen Gespräch auf ihre Gefühle des permanenten Abschiednehmens der geliebten Person eingegangen werden, auf ihre Trauer und Wut. Erst dann wird die Grundlage gelegt, damit gemeinsam im Sinne eines verhaltenstherapeutisch-systemischen Settings Lösungsstrategien gefunden werden können. Begleitung von Demenzerkrankten und ihren Angehörigen bedeutet somit nicht nur Case-Management und Beratung, wobei auch dies von großer Wichtigkeit ist, sondern sich Einlassen auf die veränderte Beziehung und Situation. Dann kann Resilienz entstehen, welche Voraussetzung dafür ist, dass die langdauernde Krankheit, die mit einem permanenten Abschiednehmen verbunden ist, gemeistert werden kann.

Sign in / Sign up

Export Citation Format

Share Document